Abstracts (complete list) - Wissenschaft Online

Jan Hendrik Niess, Frank Leithauser, Guido Adler, Jörg Reimann
Commensal-driven local TH17 responses trigger inflammatory
bowel disease
The gastrointestinal immune system has evolved to respond to a vast array of stimuli
for the innate and adaptive immune system derived from the enteric microflora. To
determine if the development of TH17 cells in the colonic lamina propria (cLP) depends
on the enteric microflora CD4 T cells that can be induced to secrete IL-17A were
isolated from the lamina propria of B6 mice housed under standard pathogen free (SPF)
or syngeneic (age- and sex-matched) germ-free (GF) mice. Increased numbers of CD4
TH17 cells were found in the lamina propria of the ileum and colon but not the
duodenum, jejunum, mesenteric lymph nodes, spleen or liver of SPF mice. In syngeneic
(age- and sex-matched) GF mice, the absence of the commensal bacteria in the gut
correlated with low numbers of cLP CD4 TH17 cells demonstrating that the microflora is
required for the accumulation of IL-17-producing CD4 T cells in the cLP. Studies in
genetically deficient, congenic SPF mice indicated that (type I and type II) interferons
suppress but IL-4 and IL-12p40-containing cytokines support the accumulation of CD4
TH17 cells in the cLP. cLP CD4 TH17 cells produce IL-17 but not IFNγ, IL-4 or IL-10.
Colitis can be readily induced by adoptive CD4 T cell transfer into congenic,
immunodeficient SPF hosts characterized by progressively increasing numbers of CD4
TH17 cells that ‘spontaneously’ produce abundant amounts of IL-17 which can be
further accelerated by transfer of IFNγ-deficient CD4 T cells into immunocompromised
SPF recipients. In absence of the enteric flora naïve CD4 T cells failed to proliferate in
transplanted GF but not in SPF hosts. Increased IL-17 levels were only found in sera of
SPF but not GF hosts and thus immunocompromised GF recipients lacking the enteric
flora are protected from the development of colitis. A deregulated, commensal bacteriadriven
local expansion of CD4 TH17 cells is a key feature of the inflammatory bowel
disease in this model and the increased numbers of TH17 cells in the cLP may restrict
the potential harmful action of the enteric flora to the local microenvironment.